Cytokine-mediated immunotherapy following autologous bone marrow transplantation in lymphoma and evidence of interleukin-2-induced immunomodulation in allogeneic transplants.
OBJECTIVE
Relapse remains a major problem following treatment of hematologic malignancies and metastatic solid tumors with allogeneic and autologous bone marrow transplantation (alloBMT and autoBMT). Our goal was to introduce posttransplantation immunotherapy for eradication of tumor cells that escape high-dose chemoradiotherapy prior to transplantation.


METHODS
Murine B-cell leukemia in BALB/c mice was used to develop a preclinical model to study the role of cytokine-mediated immunotherapy and allogeneic cell-mediated immunotherapy with donor lymphocytes in minimal residual disease (MRD). Based on these studies, a clinical trial was initiated to investigate the safety and efficacy of treating lymphoma patients with recombinant interleukin-2 (rIL-2) and interferon-alpha (IFN-alpha) at the stage of MRD following autoBMT. The clinical application of donor lymphocyte infusion (DLI) was also investigated for treatment and prevention of relapse following alloBMT. Patients in relapse following alloBMT who were resistant to DLI were treated with DLI plus rIL-2 in an attempt to activate the alloreactive potential of immunocompetent donor lymphocytes.


RESULTS
High-dose rIL-2 was effective against MRD in BALB/c mice, and the combination of rIL-2 and IFN-alpha resulted in synergistic effects even at doses of rIL-2 that were ineffective when given alone. In this animal model, graft-versus-leukemia/lymphoma (GVL) effects were induced by DLI after alloBMT and could be potentiated by coadministration of rIL-2. In clinical studies, rIL-2 plus IFN-alpha significantly improved relapse rate and survival in lymphoma patients treated after autoBMT. Relapse following alloBMT was successfully treated with DLI, and a proportion of patients who failed to respond to DLI could be salvaged with a combination of DLI and low-dose rIL-2.


CONCLUSIONS
Following autoBMT, GVL effects may be induced with a combination of rIL-2 and IFN-alpha, resulting in a reduced rate of relapse. The combination of both allogeneic donor lymphocytes and rIL-2 seemed synergistic. Because DLI plus rIL-2 was effective, even following failure of myeloablative conditioning, future strategies for treatment of leukemia should be based on T-cell-dependent immunotherapy rather than high-dose chemoradiotherapy.
Slavin
S
S
Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
Nagler
A
A
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D018572:Disease-Free Survival; D006689:Hodgkin Disease / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D015448:Leukemia, B-Cell; D017710:Lymphocyte Transfusion / Q000379:methods; D008228:Lymphoma, Non-Hodgkin / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010865:Pilot Projects; D011994:Recombinant Proteins; D016896:Treatment Outcome
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins